Down Syndrome is the most common known genetic cause of mental retardation. The major goal of this program is to understand the genetic and biologic bases of mental retardation in Down Syndrome. Building on the increasing large body of information on Down Syndrome, from the genetics to the clinical features, this program utilizes recombinant DNA technology, comparative genetics, and animal models in attempts to identify and characterize the genes involved in the Syndrome, particularly those producing the neurobiological and cognitive deficits. Also, utilizing some of the animal models, neuropharmacological interventions are proposed in attempts to ameliorate the learning and memory deficits that have been demonstrated in these animals. These animal-based efforts will ultimately lead to therapies for the neurobiological and cognitive deficits characteristic of Down Syndrome. Finally, we propose a new study combining cytogenetic, molecular and epidemiological approaches to address factors that may predispose to non-dysfunction of chromosome 21 and the genetic basis of the phenotypic consequences of an additional chromosome 21.